Transdermal devices for the delivery of a wide variety of biologically active agents have been known for some time and representative systems which utilize rate controlling membranes and in-line adhesives are disclosed in U.S. Pat. Nos. 3,598,122; 3,598,123; 3,742,951; 4,031,894, 4,144,317; 4,201,211 and 4,379,454 which are incorporated herein by reference. Such devices generally comprise an impermeable backing, a drug or active agent reservoir, a rate controlling membrane and a contact adhesive layer which can be laminated or heat sealed together to produce a transdermal delivery device.
It has also been proposed to deliver nicotine transdermally to aid in the cessation of smoking, see for example U.S. Pat. Nos. 4,597,961 and 4,839,174 which are incorporated herein by reference.
Although subsaturated systems are known, for example, U.S. Pat. Nos. 4,379,454 and 4,797,284, it is generally desirable that the agent reservoir comprise the agent to be delivered in a suitable carrier at a concentration above the saturation concentration in the carrier. This is done to maintain a unit activity source of the agent so that the delivery rate of the agent will remain substantially constant over the intended administration period, the amount of agent originally present over saturation being the depot or reservoir for the dose of agent ultimately delivered. If the concentration of the agent drops below unit activity during the delivery period, the rate of agent delivery will exhibit a corresponding decrease. It is also generally desirable to minimize the residual agent in the device after use. To accomplish this, devices normally utilize as a carrier, a material which has limited solubility for the agent to be delivered.
Although the devices of the prior art have been found useful for the delivery of a wide variety of agents, we have encountered significant problems in producing devices intended to deliver nicotine, an oily, liquid material having a high solubility in medically acceptable contact adhesives, at a substantially constant rate over the desired administration period.
As used herein, the expression "high nicotine solubility" as it relates to adhesives, is used to mean that nicotine is soluble in the adhesive to the extent that, at saturation, the adhesive layer is, (a) dissolved by nicotine; (b) becomes plasticized to the extent that it loses its cohesiveness or adhesiveness; or (c) contains concentrations of nicotine that produce adverse biological reactions when maintained in contact with the skin.
Regardless of the initial, as manufactured, concentration of active agent in the reservoir and other elements of typical prior art transdermal devices, such devices will equilibrate upon standing and the body contacting surface of the device will ultimately contain the agent at the same thermodynamic activity as the reservoir and other elements of device. Thus, when the agent is nicotine and even if the device is manufactured with a nicotine-free adhesive, we have observed that substantial quantities of nicotine will migrate from a saturated nicotine reservoir through the rate controlling membrane and into the adhesive layer prior to use.
As a result, a substantial amount of nicotine was found in the adhesive layer when applied to the skin which would be delivered through the skin in an uncontrolled manner before the rate controlling membrane exerted its effect on the nicotine remaining in the reservoir. Also, these high concentrations of nicotine in the adhesive layer and in direct contact with the skin may cause irritation or sensitization or produce undesirably high nicotine plasma levels during the initial period after application to the skin and prior to depletion of the initial loading of nicotine in the contact adhesive layer. In addition to the deleterious effects on the subject which may be caused by high concentrations of nicotine in the adhesive, most adhesives have their physical and adhesive properties degraded by such high concentrations of nicotine.
According to our invention, we have provided a rate controlled transdermal nicotine delivery device having an in-line adhesive. The device overcomes problems associated with delivering nicotine transdermally, which include irritation, sensitization and potential over dosage due to high concentrations of nicotine in the in-line adhesive and the adverse effects such concentrations can have on the physical and adhesive properties of the adhesive. The device also overcomes the shortcomings associated with oral or buccal nicotine dosage forms, such as the indigestion or jaw soreness associated with nicotine chewing gum.